Risk factors for predicting central lymph node metastasis in papillary thyroid microcarcinoma (CN0): a study of 273 resections

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1 European Review for Medical and Pharmacological Sciences 2017; 21: Risk factors for predicting central lymph node metastasis in papillary thyroid microcarcinoma (CN0): a study of 273 resections M. LI 1, X.-Y. ZHU 2, J. LV 1, K. LU 1, M.-P. SHEN 3, Z.-L. XU 4, Z.-S. WU 1 1 Department of General Surgery, Nanjing Hospital of Traditional Chinese Medicine, No.3 Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China 2 Department of Urology Surgery, Nanjing Hospital of traditional Chinese Medicine, No.3 Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China 3 Department of Thyroid Surgery, The first Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China 4 Hohai University Hospital, Hohai University, Nanjing, Jiangsu Province, China Min Li and Xiaoyu Zhu contributed equally Abstract. OBJECTIVE: The role of routine central lymph node dissection (CLND) for clinically central lymph node negative (CN0) papillary thyroid microcarcinoma (PTMC) remains uncertain. We aim to determine the predictive factors for central lymph node metastasis (CLNM) in papillary thyroid microcarcinoma. PATIENTS AND METHODS: A total of 273 patients diagnosed with clinically central lymph node negative PTMC from 2014 to 2016 were included. The predictive risk factors for CLNM were analyzed with respect to age, sex, tumor size, tumor multifocal, lymphadenectasis of lateral neck, capsular invasion, extra capsular spread (ECS), coexistence of chronic lymphocytic thyroiditis (Hashimoto thyroiditis, HT) and nodular goiter (NG), BRAFV600E mutation and subtype of papillary thyroid carcinoma (PTC). Univariate and multivariate analyses were performed to identify the risk factors for CLNM. RESULTS: Among the 273 patients, the CLNM occurred in 80 patients (29.3%). By univariate and multivariate analyses, tumor size (OR 2.07; p<0.001), multifocal (OR 2.67; p<0.004), lymphadenectasis of lateral neck (OR 9.28; p<0.001), tumor extent (OR 42.01; p<0.001) were independently correlated with CLNM. In further study, dorsal part of solitary lesion (OR: , 95%CI: , p=0.001), capsular invasion (OR: , 95% CI: , p<0.001), 6<D 9 (OR: 8.400, 95% CI: , p=0.006) and D=1 (OR: , 95% CI: , p=0.002) were more tended to have CLNM. CONCLUSIONS: A prophylactic central lymph node dissection should be considered particularly to PTMC patients with each of tumor size > 6 mm, dorsal part of solitary lesion, multifocal, lymphadenectasis of lateral neck and capsular invasion. Key Words Papillary thyroid microcarcinoma, Lymph node metastasis, Tumor, CN0. Introduction According to the World Health Organization classification system for thyroid tumors, papillary thyroid microcarcinoma (PTMC) is defined as a papillary thyroid carcinoma (PTC) of which the greatest diameter is less than or equal to 1 cm 1. With the continuous development of diagnostic imaging such as computed tomography, magnetic resonance imaging and ultra-sonography, the detection rate of PTMC has been increased 2. Although PTMC has an indolent course, the cervical lymph node metastasis (CLNM) of PTMC was reported from 12.3 to 64.1% of patients. Moreover, it was associated with local recurrence and distant metastasis 3-5. However, the role of routine central lymph node dissection (CLND) for PTMC remains uncertain according to no differences between CLND or not in prognosis 6. In addition, CLND can raise the rate of postoperative hypocalcemia. Thus, better knowledge about the risk factors for CLNM may guide clinical decisions to regard which case requires CLND. The purpose of this study was to determine the risk factors predictive of CLNM in PTMC using a retrospective cohort study. Patients and Methods Patients This retrospective cohort study consisted of 273 patients with PTMC who were treated in Nanjing Hospital of traditional Chinese Medicine from June 2014 to June This study was approved by the Ethics Committee of Nanjing Hos- Corresponding Author: Zhaoshu Wu, MD; zhaoshuwu2117@126.com 3801

2 M. Li, X.-Y. Zhu, J. Lv, K. Lu, M.-P. Shen, Z.-L. Xu, Z.-S. Wu pital of Traditional Chinese Medicine. Signed written informed consents were obtained from all participants before the study. All of the 273 patients underwent US examination before operative to detect the size of tumor and presence of LNM. Patients with unilateral PTMC underwent total thyroidectomy (TT) or unilateral lobectomy plus isthmusectomy and ipsilateral central lymph node dissection (CLND). Patients with bilateral PTMC underwent TT and bilateral prophylactic CLND. Patients with isthmus PTMC underwent TT and bilateral prophylactic CLND. Lateral compartment lymph node dissection (LLND) was selectively performed if lymph node suspicious for metastases was found before or at the time of operation. All PTMCs were proved by histological diagnosis. Methods According to central compartment lymph node status, patients were divided into two groups: CLNM (+) group and CLNM (-) group. The association between CLNM and the clinical and pathological factors such as age (< 45 and 45), gender (female and male), tumor size (0 < D 3, 3 < D 6, 6 < D 9, D = 1), location of the primary tumors (multifocal lesions, solitary lesion), tumor extent (within capsule, capsular invasion, ECS), accompanying disease (NG, HT), BRAF- V600E mutation and subtype of PTC (follicular variant, ordinary) were analyzed. Hypocalcemia was defined as total calcium < 8.0 mg/dl, corrected for serum albumin concentration. Permanent hypocalcemia was defined as a low total calcemia concentration requiring calcium supplementation for > 6 months after surgery. Postoperative vocal fold palsy, chyle leakage, and hematoma, were also investigated. Statistical Analysis The statistical analysis was performed using SPSS 17.0 (Version X; IBM, Armonk, NY, USA) software. x 2 test and Fisher s exact test were used to evaluate differences between qualitative variables. Logistic regression analysis was performed to identify the multivariate correlates of CLNM. The p-value of < 0.05 was considered statistically significant. Table I. Characteristics of patients with papillary thyroid microcarcinoma. Characteristics No. (%) Characteristics No. (%) Age (years) 43.7 ±13.1 a Tumor extent 28 (10.3) < (60.8) Within capsule 253 (92.7) (39.2) Capsular invasion 17 (6.2) Gender ECS 3 (1.1) Female 214 (78.4) Accompanying disease Male 59 (21.6) NG Tumor size Present 63 (23.1) 0< D 3 30 (11.0) Absent 210 (76.9) 3< D (37.7) HT 6< D 9 80 (29.3) Present 42 (15.4) D = 1 60 (22.0) Absent 231(84.6) Location of the primary BRAFV600E tumors Positive 115 (42.1) Multifocal lesions 111 (40.7) Negative 158 (57.9) In both lobes 61 (55.0) Subtype In one lobe 44 (39.6) Follicular variant 4 (1.5) In isthmus and lobe 6 (5.4) Ordinary 269 (98.5) Solitary lesion 162 (59.3) Lymphadenectasis of Isthmus 4 (2.4) lateral neck Others 158 (97.5) Present 36 (13.2) Upper third 53 (33.5) b Absent 237 (86.8) Middle third 66 (41.8) b Lower third 39 (24.7) b Surface part 31 (19.6) b Middle part 93 (58.9) b Dorsal part 34 (21.5) b a Mean±standard deviation. b the total is 158. D: maximal diameter of lesion. ECS: extracapsular spread. NG: Nodular goiter. HT: Hashimoto s thyroiditis. 3802

3 Risk factors for predicting CLNM in PTMC Results The clinical and pathological characteristics were summarized in Table I. Among the 273 patients with PTMC treated in our hospital, there were 214 (78.4%) females and 59 (21.6 %) males at the mean age of 43.7 ± 13.1 years (range from 18 to 81 years). 162 (59.3%) patients had solitary lesion and 111 (40.7%) patients had multifocal lesions. 61 (55.0%) patients presented bilateral lesions. 28 (10.3%) patients were characterized by local infiltration. CLNM occurred in 80 (29.3%) patients. The prognostic results of papillary thyroid carcinoma were positive. Generally, patients can survive for more than 10 years. During the follow-up, no patient died. By univariate analysis, CLNM presented a significant association with tumor size (p<0.001), multifocality (p<0.001), lymphadenectasis in lateral neck (p<0.001) and tumor extent (p<0.001). There were no significantly differences in age, gender, BRAFV600E mutation and subtype of PTC (p>0.05) (Table II). Multivariate analysis revealed that tumor size (OR: 2.07, 95% CI: 1.42 to 3.01, p<0.001), multimodality (OR: 2.67, 95%CI: 1.36 to 5.24, p=0.004), lymphadenectasis in lateral neck (OR: 9.28, 95% CI: 3.73 to 23.12, p<0.001), tumor extent (OR: 4.97, 95% CI: 1.24 to 19.91, p=0.024) remained independent variables predictive of CLNM (Table III). Furthermore, comparisons were made between CLNM and tumor size, degree of tumor invasion, multifocal, location of solitary tumor. Dorsal part of solitary lesion (OR: , 95% CI: , p=0.001), capsular invasion (OR: , 95% CI: , p<0.001), 6<D 9 (OR: 8.400, 95% CI: , p=0.006) and Table II. Relationship of factors for CLNM. Parameters CLNM (+) n=80 CLNM (-) n=193 p-value Age (year) < (60) 118 (61.1) (40.0) 75 (38.9) Gender Female 62 (77.5) 152 (78.8) Male 18 (22.5) 41 (21.2) Tumor size (mm) 0<D 3 28 (14.5) 2 (2.5) <0.001* 3<D 6 82 (42.5) 21 (26.2) 6<D 9 50 (25.9) 30 (37.5) D=10 33 (17.1) 27 (33.8) Multifocal Absent 30 (37.5) 132 (68.4) <0.001* Present 50 (62.5) 61 (31.6) Accompanying NG Absent 63 (78.8) 147 (76.2) Present 50 (62.5) 46 (23.8) HT Absent 70 (87.5) 161 (83.4) Present 10 (12.5) 32 (16.6) Lymphadenectasis of lateral neck Absent 53 (66.3) 184 (95.3) <0.001* Present 27 (33.8) 9 (4.7) BRAF V600E Negative 44 (55.0) 114 (59.1) Positive 36 (45.0) 79 (40.9) Tumor extent Within capsule 62 (77.5) 191 (99.0) <0.001* Capsular invasion 16 (20.0) 1 (0.5) ECS 2 (2.5) 1 (0.5) Subtype Follicular variant 79 (98.8) 190 (98.4) Ordinary 1 (1.2) 3 (1.6) *p<0.05 CLNM (+): central compartment LNM positive. CLNM (-): central compartment LNM negative. D: maximal diameter of lesion. NG: Nodular goiter. HT: Hashimoto s thyroiditis. ECS: extracapsular spread. 3803

4 M. Li, X.-Y. Zhu, J. Lv, K. Lu, M.-P. Shen, Z.-L. Xu, Z.-S. Wu Table III. Multivariate logistic regression for central compartment LNM of PTM. Variables B p-value OR 95% CI of Exp Age (year) Gender Tumor size (mm) <0.001* Multifocal * NG HT Lymphadenectasis of lateral neck <0.001* BRAFV600E Tumor extent * Subtype *p<0.05 NG: Nodular goiter. HT: Hashimoto s thyroiditis. ECS: extracapsular spread. D=1 (OR: , 95% CI: , p=0.002) were more tended to have CLNM. Results were showed in Table IV. Transient and permanent hypocalcemia developed in 44 (26.4%) and 2 (1.2%), vocal fold palsy developed in 7(4.2%), 6 cases of vocal fold palsy recovered within six months (transient vocal fold palsy). One case of vocal fold palsy persisted for more than 1 year (permanent vocal fold palsy), and injection laryngoplasty was performed. Chyle leakage occurred in one patient, it was controlled nonoperatively with a fat-free diet. Discussion There is an increasing incidence of PTMC in Asia and all over the world through the improved methods and extensive use of diagnostic imaging 7,8. Although PTMC has a good prognosis, the incidence of CLNM has been demonstrated in 30-60% and locoregional recurrence rates up to 20% 9,10. Because of little prognostic benefit and postoperative transient hypocalcaemia, routine prophylactic CLND for PTMC has been debated Though some researches declared that Table IV. Relationship of factors for CLNM. Parameters CLNM (+) CLNM (-) OR (95%CI) p-value Multifocal lesions In both lobes 29 (47.5) 32 (64.0) 1 In one lobe 29 (47.5) 15 (30.0) ( ) In isthmus and lobe 3 (4.9) 3 (6.0) ( ) Solitary lesion Isthmus 2 (1.5) 2 (6.7) ( ) Others 130 (98.5) 28 (93.3) 1 Upper third 41 (31.5) 12 (42.9) 1 Middle third 56 (43.1) 10 (35.7) ( ) Lower third 33 (25.4) 6 (21.4) ( ) Surface part 29 (22.3) 2 (7.1) 1 Middle part 85 (65.4) 8 (28.6) ( ) Dorsal part 16 (12.3) 18 (64.3) ( ) 0.001* Tumor extent Within capsule 191 (99.0) 62 (77.5) 1 Capsular invasion 1 (0.5) 16 (20.0) ( ) <0.001* ECS 1 (0.5) 2 (2.5) ( ) Tumor size 0<D 3 28 (14.5) 2 (2.5) 1 3<D 6 82 (42.5) 21 (26.2) ( ) <D 9 50 (25.9) 30 (37.5) ( ) 0.006* D=1 33 (17.1) 27 (33.8) ( ) 0.002* *p<0.05 CLNM (+): central compartment LNM positive. LNM (-): central compartment LNM negative. D: maximal diameter of lesion. ECS: extracapsular spread. ECS: extracapsular spread. 3804

5 Risk factors for predicting CLNM in PTMC CLNM did not affect survival, more and more studies 17 reported regional LNM was in connection with increased local recurrence rates and reduced survival. The frequency of permanent complications was low in our work. With permanent hypocalcaemia in 1.2% and permanent vocal fold palsy in 0.6%. In previous studies, CLND did not increase permanent complications. Considering the low frequency of permanent complications, we suggest that prophylactic CLND is safe in experienced hands, but its prognostic benefit has not been proven. Therefore, it is really important to investigate the association between clinic pathologic factors and subclinical CLNM.As we known, the sex, size, multifocal and capsular invasion are all predictive factors for CLNM in patients with PTMC 18. While in our work, we found no statistical correlations between age, gender, concomitant disease, BRAF V600E mutation, subtype of PTC and CLNM. Although 45-year-old is widely used as a clinical marker 19,20, researches studies reported that no association was found between age and LNM in patients with PTMC Our study shows that age is not predictive factor of CLNM. While male gender has previously been suggested as an indicator for LNM in previous investigations 20,24, the current paper showed that gender was not predictive of CLNM. There were few studies examined the effect of coexisting HT and NG with PTC on the LNM. Most of them reported negative results about the association between HT and CLNM 25. Zhao et al 26 showed negative association between NG and CLNM. Also, we found no significant difference between HT, NG and CLNM. The association between clinic pathologic factors of PTC and BRAFV600E mutation has been extensively studied in the last decade 27. However, it is still controversial now. BRAFV600E mutation has been reported to be correlated with multifocality, extrathyroidal extensive, LNM, and histological subtype in an advanced stage 28. In contrast, others found no relationship between BRAFV600E mutation and CLNM 29 and our study demonstrated a negative result. Some previous works reported that subtype of PTC is not associated with CLNM in patients with PTMC 26,30, which was similar to our research. In the present investigation, we demonstrated that tumor size > 6 mm, multifocality, lymphadenectasis in lateral neck and capsular invasion, were independent predictors for CLNM of PTMC. Generally, CLNM is associated with a larger tumor size. Lim et al 21 demonstrated that tumor size, which was larger than 5 mm, had a stronger relationship with CLNM compared with less than 5 mm. Some researches 30,31 observed that PTMC with tumor size > 7 mm was frequently associated with poor prognosis. In this study, we have confirmed that tumor size > 6 mm was an independent predictor of CLNM by comparing four different diameters of PTMC. However, the association between multifocality and CLNM remains controversial. In this study, multifocality occurred in 40.7% of 273 PTMCs, and 62.5% of them had CLNM, which was similar to other studies 32,33. In addition, multifocal PTC may grow from the clonal selection of a preneoplastic field, which may spread throughout the thyroid gland and result in CLNM 34. By univariate and multivariate analysis, we showed that multifocal was an independent predictor of CLNM. However, there is no difference between bilateral multiple cancers, unilateral multiple cancer and isthmus with lateral lobe cancer. Specifically, by comparing different locations of solitary tumor, we found that dorsal part of solitary lesion is tended to have CLNM. Cervical lymph node metastasis occurs first to central compartment and subsequently to lateral neck. The skip metastasis to lateral neck in defect of CLNM is uncommon 35,36. By comparing the preoperative lymph node status of lateral compartment and CLNM, lymphadenectasis in lateral neck was discovered as an independent risk factor for CLNM. Besides, lateral LNM was presented in 30 (83.3%) patients and 27 patients (90.0%) present both positive lateral LNM and positive CLNM. Capsular invasion is traditionally thought to be predictive for CLNM 18. In this research, Capsular invasion was not rare (13.7%), which is consistent with the rate reported by previous studies ( %). Therefore, our research proved that, once again, Capsular invasion is an important prognostic characteristic of CLNM. Also, ECS is considered to be predictive for CLNM. However, in our study, we get an opposite result, it may contribute to adequate number of cases. Conclusions We showed that tumor size > 6 mm, multifocality, lymphadenectasis in lateral neck, capsular invasion are independent predictive factors for CLNM of PTMC. Prophylactic CLND may be recommended for these aggressive PTMC patients. 3805

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